1989_Multinational Drug Companies Issues in Drug Discovery and Development [1 ed.] 088167463X

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MULTINATIONAL DRUG COMPANIES Issues in Drug Discovery and Development BERT SPILKER

Raven Press

Multinational Drug Companies: Issues in Drug Discovery and Development

Bert Spilker, Ph.D., M.D. Department Head, Project Coordination, Burroughs Wellcome Co. Research Triangle Park, North Carolina Adjunct Professor of Pharmacology and Clinical Assistant Professor of Medicine University of North Carolina Medical School Clinical Professor of Pharmacy, University of North Carolina School of Pharmacy Chapel Hill, North Carolina

Raven Press

New York

Raven Press, 1185 Avenue of the Americas, New York, New York 10036

© 1989 by Raven Press, Ltd. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronical, mechanical, photocopying, or recording, or otherwise, without the prior written permission of the publisher. Made in the United States of America Library of Congress Cataloging-in-Publication Data

Spilker, Bert. Multinational drug companies. Bibliography: p. Includes index. 1. Pharmaceutical industry. 2. Pharmaceutical industry —Technological innovations. 3. Drugs— Research — Management. 4. International business enterprises. I. Title. [DNLM: 1. Drug Industry. 2. Drug Screening. 3. Research. 4. Technology, Pharmaceutical. QV 736 S756m] HD9665.5.S68 1989 338.8'87 88-42830 ISBN 0-88167-463-X The material contained in this volume was submitted as previously unpublished material, except in the instances in which credit has been given to the source from which some of the illustrative material was derived. Great care has been taken to maintain the accuracy of the information contained in the volume. However, neither Raven Press nor the editors can be held responsible for errors or for any consequences arising from the use of the information contained herein.

To everyone in the drug industry who helps discover, develop, produce, and market new drugs of medical value.

About The Author Bert Spilker, Ph.D., M.D. is Department Head, Project Coordination at Burroughs Wellcome Co. and holds faculty appointments at the University of North Carolina in the Schools of Medicine (Departments of Medicine and Pharmacology) and of Pharmacy. Dr. Spilker has 16 years experience in the pharmaceutical industry, having worked for Pfizer Ltd. (United Kingdom), Philips-Duphar B.V. (The Netherlands), Sterling Drug Inc. (Rensselaer, New York), and the Burroughs Wellcome Co. H e has experience with a private consulting company in the Washington, DC area and has additional experience in the private practice of general medicine. Bert Spilker received his Ph.D. in Pharmacology from the State University of New York, Downstate Medical Center, and did post-doctoral research at the University of California Medical School in San Francisco. He received his M.D. from the University of Miami Ph.D. to M.D. Program and did a residency in internal medicine at Brown University Medical School. Bert Spilker is the author of over 60 publications plus several books in a wide area both of pharmacology and clinical medicine. Dr. Spilker is married and has two children.

Foreword This is a valuable book for anyone, within or without the pharmaceutical industry, who would like to understand the complexities involved in discovering and developing new drugs — what Newsweek magazine has called the “enchanted substances” that prolong and improve the quality of life. This is the first time, as far as I know, in which all of the many elements of pharmaceutical research and development are discussed in one book — medical, scientific, production, marketing, financial, legislative, and public affairs. The result is a unique overview of the various factors that must be considered in the quest to develop new and more effective medicines. The book is not a dry and technical treatise, although the technical aspects of drug discovery and development are fully covered. Rather, it is written in an interesting manner that reflects the author’s wide knowledge of literature, philosophy, history, and management. It nicely mixes the practical and the theoretical. The book clearly shows that, while pharmaceutical companies are similar in many ways to other businesses, they are also unique. A research-based pharmaceutical company is in the innovation business, involved in the long, expensive, highly risky, and highly regulated activity of finding new ways to cure and treat age-old diseases, like cancer, and new plagues, like AIDS. It is a business literally of life and death — in which we all have a stake. This book, by a physician/pharmacologist who has spent more than 16 years in research and development with four different drug companies, provides a real insight into the critical pharmaceutic R&D process.

Gerald J . Mossinghoff, President Pharmaceutical Manufacturers Association

vii

People who want to identify possible solutions to problems in drug discovery and development, to learn about current standards, and to improve their efficiency have a difficult task in finding published sources of help. Those who desire to understand the processes and issues involved in multinational drug discovery and development also have a hard time finding useful references. This book provides information that addresses those needs. The specific approaches this book uses to achieve these goals and the specific audiences targeted are described more fully at the start of Chapter 1. The book focuses on five broad topics, each dealt with in a separate section of the book. The first section covers the central issue of discovering and developing drugs. Processes are discussed along with means of enhancing the success of these activities. Section two focuses o n the corporate level and describes organizational, personnel, and future-oriented issues. It also identifies many ways in which companies differ from each other. The third section concentrates on research and development. Research and development activities are discussed from various perspectives. The discussions focus on organization, management, personnel, productivity, and efficiency issues. The fourth section presents more detailed descriptions of many technical functions and departments, including information management, toxicology, clinical, marketing, and production. Lastly, the fifth section discusses interactions and relationships between drug companies and external groups or organizations such as government agencies, academic institutions, trade associations, the press, and the public. It is hoped that this book will be useful to both experienced managers and other individuals who wish to learn more about the drug industry. Bert Spilker

ix

Acknowledgments It is a great pleasure to thank Mr. Doug Henderson-James, Dr. John Kelsey, and Dr. John Schoenfelder who reviewed the manuscript and made many valuable suggestions. The author appreciates helpful discussions with the following people, most of whom also reviewed portions of this book. Mr. Glenn Andrews, Mr. J.M. Arnold, Ms. Kathy S. Bartlett, Mr. Michael T. Burke, Dr. Donald Clive, Ms. Karen Collins, Mr. Jerry D. Crandall, Dr. Joann Data, Mr. N. Ranthi Dev, Dr. Gertrude B. Elion, Ms. Janyth Fredrickson, Dr. Charles W. Gorodetsky, Mr. Robin K. Henning, Dr. David W. Henry, Dr. Steven Jacobs, Mr. Tim Kvanvig, Mr. Al MacKinnon, Dr. Warren McAllister, Dr. Lloyd G. Millstein, Mr. David A. Moyer, Dr. Donald H. Namm, Dr. Lawrence A. Nielsen, Dr. Joel E. Sutton, Dr. Roy Swaringen, Dr. George Szczech, Dr. Hugh Tilson, Ms. Ildiko Trombitas, Mr. Glenn K. Weingarth, Dr. Thomas L. Wenger, and Mr. J.R. Whitehead. There are a number of individuals who have had a great effect on helping to formulate the author’s views over the last decade and it is a pleasure to acknowledge their contributions. They are Drs. Allen Cato, Gilles Cloutier, Pedro Cuatrecasas, Howard J. Schaeffer, and S. Winston Singleton. Excellent editorial help of Mr. Allen Jones, assistance with literature searches by Mr. Roily Simpson, and illustrations by Ms. Jacqueline Jenks are appreciated. A very special thanks is due Mrs. Joyce B. Carpunky, who cheerfully typed each of the drafts and revisions as this book took shape. The views expressed in this book are solely those of the author and do not reflect opinions or practices of any specific company, unless clearly indicated.

♦

Contents List of Tables

xv

List of Figures

xix

List of Abbreviations

xxv

Section I: Drug Discovery and Development

1. The Big Picture

3

2. The Nature of Drug Discovery and Development

27

3. How Do Scientists and Clinicians Evaluate and Interpret Data

77

4. Stimulating the Innovative Process and Increasing Efficiency of Drug Development

93

Section II: Corporate Organization and Management Issues

5. Organizing at the Corporate Level

119

6. Corporate Management

135

7. Selected Personnel Issues at the Corporate Level

165

8. Differences within and between Drug Companies

179

9. Future Environments for Drug Discovery and Development

195

Section III: Research and Development Organization and Management Issues

10. Organizing at Research Division and Department Levels xi

213

xii

CONTENTS

11. Management of Research and Development

227

12. Personnel Roles and Issues in Drug Discovery and Development

243

13. Balancing Line Function and Matrix Approaches

255

14. Choosing the Number of Drugs to Develop Simultaneously

269

15. Evaluating a Portfolio of New Drug Projects

277

16. Measuring Productivity, Innovation, and Project Success

311

Section IV: Technical and Function Issues

17. Information, Data Management, and Statistics

335

18. Toxicology Issues

351

19. The World of Clinical Studies and International Drug Development

361

20. Issues of Technical Development

399

21. Marketing Issues

419

22. Production Issues

459

23. Financial Issues

479

Section V: External Interactions and Relationships

24. Interactions and Relationships between Drug Companies and Academic Institutions

499

25. Interactions and Relationships between Drug Companies and Government Agencies

511

26. Interactions and Relationships between Drug Companies: Competition and Collaboration

529

27. Interactions and Relationships between Drug Companies and Trade Associations

541

CONTENTS

xiii

28. Interactions and Relationships between Drug Companies and Health Professionals

545

29. Interactions and Relationships between Drug Companies, Patients, and the Public

549

30. Interactions and Relationships between Drug Companies and the Media

559

Selected Books About Drug Discovery and Development or of Particular Interest to the Drug Industry

569

References

575

Subject Index

583

List of Tables Section I Table 1.1

Typical periods of time required to develop new drugs

19

Table 2.1

Selected drugs that are prepared from natural plants

31

Table 2.2

Selected examples of clinical serendipity

32

Table 2.3

Basic combinations of approaches to the three levels of therapeutic areas

36

Table 2.4

Uses of extrapolating in vivo pharmacological data from animals

43

Table 2.5

Research and development criteria to evaluate a new compound for potential development as a drug

64

Table 2.6

Activities performed on marketed drugs in research departments

67

Table 2.7

Activities performed on marketed drugs in medical departments

68

Table 2.8

Activities performed on marketed drugs in technical development and regulatory affairs’ departments

69

Selected techniques of biotechnology

73

Table 2.10 Sources of production of selected biological drugs

74

Table 2.9

Table 3.1

Table 3.2

Characteristics of an ideal clinical method for evaluating topical antipruritics

90

Characteristics of an ideal antiepileptic drug for treating partial seizures

90

Table 4.1

Selected myths of innovation

104

Table 4.2

Advantages in waiting until a generally complete profile is obtained about a chemical series before a lead compound is chosen for testing in humans, plus counterarguments

112

Advantages in taking early chemical leads rapidly into humans for testing, plus counterarguments

112

Table 4.3

XV

xvi

LIST OF TABLES Section II

Table 5.1

Selected factors that tend to increase drug company growth

131

Table 5.2

Selected factors that tend to diminish drug company growth

132

Table 6.1

Some major functions of management

148

Table 7.1

Factors influencing motivation of employees

171

Table 7.2

Characteristics of high scientific performers

172

Table 7.3

Possible reasons for low employee productivity

172

Section III

Table 11.1 Basic issues frequently considered in the management of research and development

229

Table 16.1 Parameters for measuring productivity of research and development activities

319

Table 16.2 Points designed to increase productivity and quality

325

Table 16.3 Analyses used to calculate success rates of compounds developed as drugs

328

Table 16.4 Calculating the success rates for compounds and drugs shown in Fig. 16.2

330

Section IV Table 17.1 Primary factors used to select systems and equipment to store information

339

Table 17.2 Selected drug development areas that may be automated

342

Table 17.3 Selected clinical areas of drug development that may be automated

343

Table 19.1 Selected means to increase the rate of clinical drug development

370

Table 20.1 Selected issues in the development of a drug formulation

408

Table 20.2 Selected uses of laboratory robotics

409

Table 21.1 Assessment of new products by marketing

421

Table 21.2 General types of marketing related activities in the drug industry

422

LIST OF TABLES

xvii

Table 21.3 Reasons for termination of drug projects by Hoechst-Roussel Pharmaceuticals Inc. between 1972 and 1978

423

Table 21.4 Reasons for termination of new chemical entities under development by seven United Kingdom-owned drug companies between 1964 and 1980

423

Table 21.5 Top drugs in sales of leading manufacturing companies in the United States in 1985

425

Table 21.6 Numbers of drugs constituting 50 percent of a company's sales

428

Table 21.7 Selected methods used to assess customer needs and satisfaction

436

Table 21.8 Potential methods to select trademarks

439

Table 21.9 Profile of traditional and professional types of over-the-counter drugs

446

Table 21.10 Factors that may lead to an inaccurate marketing forecast

448

Table 21.11 Possible reasons used to explain poor sales performance

455

Table 22.1 Measurement of tablet weight

468

Table 22.2 Selected production issues relating to a physical plant and its equipment

473

Table 22.3 Selected production issues relating to the processes conducted

474

Table 22.4 Selected production issues relating to people involved

474

Table 22.5 Selected production issues relating to products made

475

Table 22.6 Items to include in a synopsis of production status for individual drugs

475

Table 23.1 Research and development expenditures by function in West Germany and the United States

490

Section V Table 24.1 Types of interactions between drug companies and academic institutions

500

■w

Table 24.2 Selected biomedical relationships between universities and drug companies

501

Table 27.1 Selected activities conducted by trade associations in the United States

542

List of Figures Section I Fig. 1.1

Selected metaphors of drug discovery and development

16

Fig. 1.2

Pipeline concept of drug development

18

Fig. 1.3

Selected types of subpipelines in drug development

Fig. 1.4

“Seat-of-the-pants” drug development

23

Fig. 2.1

Major processes used to discover a new chemical lead

29

Fig. 2.2

Major sources of a new drug

30

Fig. 2.3

Selected therapeutic opportunities in cardiology for new drug development

37

Fig. 2.4

Metabolic degradation of diazepam leading to useful novel drugs

44

Fig. 2.5

Successful molecular manipulations leading to useful drugs

47

Fig. 2.6

Selected chemical groups that could be placed on a chemical backbone

48

Fig. 2.7

Types of alterations in biological activity that may be observed in a series of closely related compounds with a single chemical modification

49

Types of alterations in biological activity observed in a series of compounds with two chemical modifications

50

Scope of biological activity in compounds with modified structures

51

Fig. 2.10 Progressive improvements in histamine type-2 receptor antagonists used to treat duodenal ulcers

54

Fig. 2.11 Histamine type-2 receptor antagonists developed after cimetidine

55

Fig. 2.12 Progressive improvements in the early development of beta-receptor antagonists

56

Fig. 2.13 Spectrum of research activities in a drug company ranging from purely targeted to purely exploratory

57

Fig. 2.8

Fig. 2.9

xix

20-21

XX

LIST OF FIGURES

Fig. 2.14 Hypothetical formats for organizing multiple animal models and tests

61

Fig. 2.15 Stages of drug discovery and development

63

Fig. 3.1

Hierarchies (i.e., different levels) in the therapeutic process

79

Fig. 3.2

Hierarchies in the actions of cardiac glycosides

81

Fig. 4.1

Outputs of innovation to improve on a chemical’s activity

95

Fig. 4.2

Examples of negative tangents in a drug’s development

101

Fig. 4.3

Drugs in search of a disease

102

Section II Fig. 5.1

Functional model of an organization

122

Fig. 5.2

Product-oriented model of an organization

123

Fig. 5.3

Matrix model of an organization

124

Fig. 5.4

Business- and function-oriented model of an organization

125

Fig. 5.5

Business- and matrix-oriented model of an organization

126

Fig. 5.6

Patterns of corporate development

127

Fig. 5.7

Organizational processes that support development patterns in Fig. 5.6

128

Fig. 6.1

A scale to measure leadership practices

142-143

Fig. 6.2

Characteristics of leaders and managers

144

Fig. 6.3

A leader’s relationship to his or her group

145

Fig. 6.4

Steps that are often involved in making major corporate changes

154

Fig. 6.5

A strategic planning model

158

Fig. 6.6

Selected businesses related to ethical pharmaceuticals

159

Fig. 8.1

Characterizing the marketing position of a specific company

182

Fig. 8.2

Susceptibility of various drug companies to generic substitution

183

Fig. 8.3

Susceptibility of a particular company to generic substitution over a period of years

184

Visual models of drug development plans

185

Fig. 8.4

I

LIST OF FIGURES

xxi

Section III Fig. 10.1 Traditional discipline-oriented organization of research and development activities in a drug company

216

Fig. 10.2 Therapeutically based organization of research and development activities in a drug company

217

Fig. 10.3 Matrix (horizontal) organization of drug development project activities in a drug company

218

Fig. 10.4 Types and levels of support for drug development activities

220

Fig. 10.5 Organizational relationships and interactions between chemists and biologists in drug discovery activities

222

Fig. 11.1 Extrapolating management information and beliefs through various levels of research and development

228

Fig. 11.2 Evaluating how research and development resources are being applied to areas of company strengths and weaknesses

239

Fig. 11.3 Evaluating how research and development resources are being moved to areas of particular interest

241

Fig. 12.1 Interactions among clinicians and statisticians at different sites of a single company

250

Fig. 12.2 Support and services required when an MD joins the staff of a company

252

Fig. 13.1 Elements of the project-driven matrix management philosophy

257

Fig. 13.2 Leadership of a project team

260

Fig. 15.1 Number of new projects initiated per year

287

Fig. 15.2 Head count currently applied to a project and its commercial attractiveness

288

Fig. 15.3 Cost of development and commercial value of individual projects

289

Fig. 15.4 “Thermometer” model used to illustrate the proportion of money already spent on a project

290

Fig. 15.5 Number of regulatory submissions made per year

291

Fig. 15.6 Comparison of staff allocated to a project and expected sales of that project

292

Fig. 15.7 Probability of technical success versus commercial value of individual projects

293

xxii

LIST OF FIGURES

Fig. 15.8 Probability of technical success versus commercial value of individual projects

294

Fig. 15.9 Illustrating change in a project portfolio over a period of time

295

Fig. 15.10 Illustrating a portfolio of new drugs on the basis of the technology’s maturity

296

Fig. 15.11 Average cost of work effort on a project

297

Fig. 15.12 Illustrating a portfolio on the basis of risk

298

Fig. 15.13 Return on investment in a portfolio versus the probability of exceeding the return on investment

299

Fig. 15.14 Percent of total sales and profits derived from new products in each of several years

300

Fig. 15.15 Sales and profits of new drugs per year

301

Fig. 15.16 Percent of a company’s total sales and profits derived from new products

302

Fig. 15.17 Research expenditures on drug discovery activities required to generate a new chemical entity project

303

Fig. 15.18 Grid of market size versus level of medical need

304

Fig. 15.19 Growth share matrix illustrating four basic types of drugs or businesses

305

Fig. 15.20 Product market evolution matrix

306

Fig. 15.21 General Electric’s nine-cell planning grid of business strength versus industry attractiveness

307

Fig. 15.22 Company position versus industry attractiveness figure

308

Fig. 16.1 Tracking the time required for regulatory review and approval of new drugs

318

Fig. 16.2 Illustration of two methods for defining success based on clinical phase of development

329

Fig. 16.3 Example of determining success of projects based on the individual phase success rate

331

Section IV Fig. 17.1 Pattern of information flow

338

Fig. 19.1 Levels and sublevels of clinical studies

363

LIST OF FIGURES

xxiii

Fig. 19.2 Selected approaches to clinical drug development

369

Fig. 19.3 Planning and tracking the indications and dosage forms studied

371

Fig. 19.4 Patient participation in clinical studies

373

Fig. 19.5 Lasagna’s Law

374

Fig. 19.6 Identifying the adverse reaction

377

Fig. 19.7 Hypothetical types of reporting patterns of adverse reactions over time

382

Fig. 19.8 Models of project teams that may be used for international drug development

394

Fig. 20.1 Selected types of apparatus used to evaluate drug dissolution

405

Fig. 21.1 Interactions of physicians, pharmacists, patients, and drug companies

449

Fig. 21.2 A patient’s steps in obtaining and following medical treatment with drugs

451

Fig. 21.3 Market share for psychostimulant drugs between 1975 and 1981, illustrating a stable market

453

Fig. 21.4 Market share for antiarthritic drugs between 1976 and 1981, illustrating an expanding market

454

Fig. 22.1 Procedures of quality assurance and quality control

464

Fig. 23.1 Research and development expenditures by function

489

Fig. 23.2 Selected methods of illustrating overall expenditures within research and development

491

Fig. 23.3 Selected methods of illustrating expenditures within research and development according to function

492

Fig. 23.4 Illustration of research expenditures according to various therapeutic areas

494

Fig. 23.5 Graphing projected versus actual expenditures over a period of time

495

Section V Fig. 24.1 Levels within the drug industry and academia that may directly interact

502

Fig. 24.2 Selected areas where indirect interactions occur between academia and the drug industry

503

Fig. 25.1 Flow of regulatory dossiers between countries

516

List of Abbreviations and Terms AIDS

Acquired Immune Deficiency Syndrome.

FDA

Food and Drug Administration. Regulatory agency in the United States that must approve new drugs for marketing. Oversees many postmarketing practices of the pharmaceutical industry.

GCP

Good Clinical Practices. Unofficial term used to include proposed United States regulations governing conduct of sponsors and investigators during clinical studies. Also refers to approved United States regulations governing IRBs, INDs, and informed consents.

GLP

Good Laboratory Practices. United States regulations governing quality assurance procedures in toxicology facilities and other preclinical laboratories. Approved in 1978.

GMP

Good Manufacturing Practices. United States regulations governing quality assurance procedures in drug manufacturing. Approved in 1963.

HMO

Health Maintenance Organization. A prepaid health group.

IND

Investigational New Drug Application. FDA regulatory document allowing clinical studies to proceed on an investigational drug or investigational use of an approved market drug.

IRB

Institutional Review Board. An ethics committee that must approve protocols for human studies at the institution where they are to be done.

NCE

New Chemical Entity. A novel chemical compound that may be tested as a drug.

NDA

New Drug Application. An application to the FDA for approval of a new drug in the United States.

OTC

Over-the-counter drugs. Drugs sold without a prescription.

Phase I

Initial clinical studies in normal volunteers and sometimes patients to test a drug’s safety. XXV

xxvi

LIST OF ABBREVIATIONS AND TERMS

Phase II

Clinical studies in patients to test if the drug has the desired efficacy.

Phase III

Clinical studies in patients to gain additional safety, efficacy, and other information prior to marketing.

Phase IV

Clinical studies conducted after a drug is marketed. Includes postmarketing surveillance studies.

PLA

Product License Application. A regulatory application for any NCE outside the United States or for a biological drug in the United States.

PPO

Preferred Provider Organization. A prepaid health group.

QA

Quality Assurance. Process of validating individual steps in a toxicology study, manufacturing process, or other area.

QC

Quality Control. Process of validating the final step in manufacturing or another area.

R and D

Research and development.

USP

United States Pharmacopeia.

WHO

World Health Organization.

Section I Drug Discovery and Development

The Big Picture

The Crucial Issue Facing Drug Companies Today 4 Orientation and Approach of This Book 4 Purpose of the Book 4 Approaches Used in This Book 5 Intended Audiences 5 Overall Perspective of Drug Companies 6 Uniqueness of the Drug Industry 6 Attributes of Drug Companies 7 Drug Costs and Profits 8 Competition within the Drug Industry 8 Perspectives of Different Groups about New Drugs 9 Synopsis of Drug Discovery and Development 10 Drug Discovery 10 Drug Development 11 Influence of Regulations on Drug Discovery and Development 12 Golden Rules of Drug Development 12 Metaphors of Drug Discovery and Development 15 Pipeline of Drug Discovery, Development, and Marketing 16 Horse Race 19 Poker Game 19 Orchestra 21 Hurdles Race 22 Ocean Liner 22 Maze 22 Connect-the-Dots, Lottery, and Other Metaphors 23 High Jump 24 Functions of Drugs 24

To survive and succeed in a hot market, a company must be willing to change everything about itself except its basic beliefs . . . Give the individual full consideration, spend a lot of time making customers happy, go the last mile to do a thing right. Thomas J. Watson, Jr., former chief executive of IBM. From Fortune (August 31, 1987).

3

4

THE BIG PICTURE

THE CRUCIAL ISSUE FACING DRUG COMPANIES TODAY

For research-based drug companies the most critical issue today is maintaining a flow of new, innovative drugs that insure the company’s growth and even survival. Most drug companies are fully committed to this challenge, because the alternative of having a dry period without new products is unattractive and its consequences clear. T o meet the challenge, companies are adopting strategies of developing their drugs on a global basis utilizing state-of-the-art technologies and attempting to improve their efficiency of drug discovery and development. Companies primarily obtain their new drugs from in-house research discoveries, licensing from other companies or groups, and joint ventures with other companies. This book describes the state-of-the-art standards that exist in many aspects of drug discovery and development. Another response to the challenge of preventing dry periods without new products is to conduct a detailed analysis of the entire research and development process and seek ways of improving current systems, organizational structures, and approaches. These internal evaluations used to occur approximately once in a five- to ten-year period and often involved an outside consulting firm. At the present time, this process tends to occur on a more frequent or even on a continual basis. This book provides specific techniques to help managers judge a company’s strengths and weaknesses and many detailed methods used to analyze a drug company or its research and development activities are presented. The world of drug discovery and development is rapidly changing, and there is a need for companies to take a broad view to develop useful strategies and take advantage of opportunities. The information explosion in the published literature provides details of technical aspects of drug discovery and development on a daily basis. The press, trade associations, and numerous other sources provide information about the drug industry as a whole (or selected parts) to the public and to health professionals. There are no sources, however, that provide a broad view of the issues of drug discovery and development from a specific company’s perspective. That is the intention of this book.

ORIENTATION AND APPROACH OF THIS BOOK

This book examines many issues unique to discovering and developing drugs. Although its primary focus is on research and development, this book includes consideration of overall corporate issues as well as specific issues relating to marketing, production, financial, legislation, public affairs, and other areas.

Purpose of the Book

This book has two major objectives— to present both specific and general information on issues faced within a company during drug discovery and development. The specific information is intended to help both experienced and inexperienced

THE BIG PICTURE

5

individuals in the drug industry perform their own work more effectively and better understand other areas with which they interact. The general information is intended to help individuals either within or outside the drug industry achieve a better understanding and awareness of the operations and issues faced by the entire company or by a specific part of that company. A discussion of various means of addressing issues and problems is also presented. Both specific and general standards used in drug discovery and development are mentioned and discussed. Approaches Used in This Book

Most issues are not covered in great depth for two reasons. First, the book would expand to many times its present length, and second, almost every situation that arises regarding drug discovery and development differs in some aspects from those that have been previously experienced. One advantage of the broad approach of this book is that it allows the reader to view a wide range of drug discovery and development issues from a single perspective. Both practical and theoretical information is presented as a guide to both understand and improve the inner workings of a drug company. The specific approach used in this book is to present and discuss a mixture of concepts, problems, state-of-the-art procedures, and considerations that may influence decisions. Numerous examples, tips, approaches, suggestions, options, and opinions are offered to help the reader select those pieces of information of greatest value. Intended Audiences

Many senior and junior positions in a pharmaceutical company’s hierarchy are held by executives who have little formal scientific training. The fundamental ways in which the drug industry differs from other industries (e.g., long time required to develop drugs, uncertainty of a drug’s future, impossibility of making many decisions on a quantitative basis, the necessity of making decisions with incomplete information) are not fully understood by many of them. Some of these individuals, however, often must make decisions involving research or development issues. This book is intended to provide knowledge and indicate considerations that those individuals require to make informed decisions. It presents a broad overview of the drug development process using a common sense approach to help these nonscientists, as well as other nonscientists in a drug company, gain a better understanding of many scientific and nonscientific issues. This book is also directed to scientists and clinicians directly involved in drug discovery and development. These people may be located in industry, government, or academia; or they may function as independent consultants or contractors. Most of these individuals work in one discipline and do not deal with the broad spectrum of issues found in drug discovery and development. By placing most of the issues that they deal with in a broader perspective, this book will allow them to see how their work fits into the overall process.

6

THE BIG PICTURE

The issues discussed are also addressed to professionals and health care workers in government agencies, trade associations, academic centers, hospitals, and other places who interact with the drug industry. Many interactions are described in this book in separate chapters devoted to government agencies, trade associations, and academic institutions. This book should help these individuals who are not employed in the drug industry better understand the nature and complexity of many issues faced during drug discovery and development. The chapters of this book are self-contained and may be read in any order. Entire books have been written on the subjects of many of the individual chapters. The information in this book is based on the author’s experiences at four drug companies, the literature, and communications with individuals employed at many companies; it is not a reflection of any single company. OVERALL PERSPECTIVE OF DRUG COMPANIES Uniqueness of the Drug Industry

It is critically important for senior executives to have a detailed understanding of their industry. This helps them reach more informed and sometimes better decisions about many important issues, policies, and questions that frequently arise. Yet, one often reads speeches of a drug company’s chief executive or senior company officers who may be top lawyers, financiers, or marketing experts, but do not understand the basic concepts and processes of how drugs are discovered and developed. The various factors that influence drug discovery and development may also not be well understood. Although most companies may be operated and managed as if they make “widgets,” a drug company must not. Major factors that differentiate drug companies from other companies are listed below. Some of these factors are only a matter of degree (1) the long period of time required to develop and market a newly discovered drug, (2) the high degree of financial risk and uncertainty of a drug’s future, even after it is launched, (3) the large number of highly restrictive regulations that govern all aspects of a drug’s development, production, and marketing, (4) the inability to predict when the next important drug discovery will occur, and (5) the large number of variables and factors that are involved in biological experiments, technical development, and especially clinical studies. This last point means that a large number of interpretations are possible in many situations. Each of these critical aspects requires an understanding of the drug discovery and development process. It is also important to understand the factors that relate to creating and maintaining an appropriate environment in which drug discovery may occur. The drug industry shares some characteristics with many other industries, including other high technology industries. 1. A rapidly changing environment in which products are sold. Many of these changes are highly unpredictable, both in the nature and rate of change. 2. Competition in many areas including product discovery, development, and marketing.

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Many aspects of the corporate environment in which these activities take place are nuances of the corporate culture. Corporate culture shapes the strategies used by a company to develop drugs and is discussed in several other chapters of this book. This culture-strategy interaction is also discussed by Shrivastava and Guth (1985).

Attributes of Drug Companies

Many individuals, especially those who have limited time to devote to an issue or question, want to understand “the big picture.” In some circles this cliche is as common as “the bottom line” (i.e., the overall impression or amount). The big picture obtained after looking at a drug company includes consideration of its (1) core and other businesses, (2) overall size, (3) current and planned activities, (4) profitability, (5) approaches to drug discovery and development, and (6) current portfolio of marketed and investigational drugs.

Core and Other Businesses Is the company strictly a pharmaceutical company, a health care company, or a company engaged in a wide variety of businesses? If the latter, how does the drug business fit into the company’s overall mission?

Overall Size This aspect may be described in terms of sales per year, numbers of workers, assets, or other factors. Size does not necessarily correlate with profit or number of drugs marketed. This topic is described more in Chapter 5.

Current and Planned Activities This aspect primarily relates to whether the company is research based or generic, is development oriented (i.e., licenses-in most or all of its drugs), or is a biotechnology company. This topic is described throughout this book.

Profitability The relative profitability of a drug company may be based on a comparison with other drug companies, or a between-industry comparison with other companies of the same size. A few means of illustrating a company’s profitability are illustrated in Chapter 15 and establishing drug prices in Chapter 21.

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Companies vary from those that utilize highly formal approaches to drug development to those that emphasize flexibility. This aspect is described throughout this book. Organizational structures are primarily described in Chapters 5 and 10. Current Portfolio of Marketed and Investigational Drugs The portfolio of marketed drugs may include both multisource (i.e., drugs susceptible to generic competition), patent protected, or otherwise protected (e.g., with exclusivity under the Orphan Drug Act) drugs. Drugs under development (i.e., investigational drugs) are assessed by the medical and commercial value of the company’s portfolio of potential new products (see Chapter 15). Drug Costs and Profits

A significant part of the “big picture” relates to profits. Food and Drug Administration (FDA) regulations and guidelines since 1962 have required many more premarketing studies to be conducted than previously. Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP) regulations have also increased costs of bringing a new drug to market. Regulations, however, are only one of many factors that have resulted in higher prices charged for drugs. Other factors include the steadily mounting costs for laboratory equipment, clinical studies, staff salaries, and other components of drug discovery and development. As a result of increased health care expenditures during the 1960s and 1970s, the government reacted. It has taken various steps (e.g., encouraging generic competition, passing maximum allowable cost regulations, providing bonuses to pharmacists who dispense generic drugs) to force drug prices down. Food and clothing prices, however, have been kept artificially high by government price support programs for agriculture and tariffs and import quotas on foreign textiles. The major reason why drug companies are willing to invest hundreds of millions in high-risk research is that the rates of return for the few commercially successful drugs are also high. If the rates of return are markedly diminished, as is already occurring in some countries, drug companies will be much less willing in the future to invest their money in research. Economic analyses clearly show that if regulations diminish profits for drug companies on their few successful drugs below a certain minimum, the companies will reduce investments they are willing to make in research. Without sufficient research, drug discovery will slow and this will decrease the rate at which new drugs will reach the market. Competition within the Drug Industry

An additional piece of the “big picture” is the risk from competition. Competition within the drug industry exists on several levels. These include (1) being first to enter new therapeutic markets, (2) price and other types of competition (e.g., perceived benefits) on similar products within a single therapeutic market, and (3) man-

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ufacturing generic versions of the same drug. The evidence that supports the view that there is significant competition in the drug industry includes (1) price flexibility on specific products; (2) instability of market share over a period of a few years; (3) high rate of corporate mergers, buyouts, and bankruptcies; and (4) licensing arrangements. The drug industry has the second highest rate of market share instability of all industries in the United States (Schnee and Caglarcan, 1978).

Perspectives of Different Groups about New Drugs

When drug discovery and development issues are being presented and discussed, numerous perspectives could be used. These include those of various groups both within and outside the drug industry. Representative groups within the industry would include people in marketing, production, science, medical, and technical development functions. Representative groups outside the industry include patients, physicians, and regulatory agencies. Most of this book presents the perspectives of those within the industry. Nonetheless, it is useful to briefly review the perspective of some groups from both within and outside the industry.

Perspectives about New Drugs by Groups within the Drug Industry Perspectives of drug company employees about new drugs are somewhat influenced by their background and discipline within their company. Informed and knowledgable people view drugs in terms of a combination of medical, scientific, and commercial parameters. Others focus more on one of these (or other) aspects of a new drug. Many groups within and outside the drug industry often ascribe a logic to a drug’s discovery or its development that is actually a convenient teleological explanation. Events usually seem more clear in hindsight when numerous activities are rearranged in people’s minds, rough edges are smoothed out, and loose threads (e.g., false leads and approaches) are conveniently forgotten or ignored. As a result, the story of many drug’s discovery and development appears logical and orderly, whereas many false turns, accidents, mistakes, and luck were involved. Lucky errors may have directed the drug along the right path to its success. Many drug discoveries have occurred and paths of development correctly followed despite some people’s attempts to proceed in a different direction. There are some noteworthy exceptions to this somewhat cynical view, that illustrate a logical and stepwise approach to drug discovery and development. People in each company often talk about new upcoming drugs much as company stocks are described. The perceived value of a drug to a company often has precipitous changes based on casual or formal comments from the FDA, investigators, or company scientists. These changes are often more related to emotional reactions to the drug’s characteristics, uninformed judgments, or other reactions that do not reflect the drug’s true value. The perceived value of a drug to stockbrokers and to stockholders in terms of eventual profit also rises and falls precipitously based on news, which may or may not be accurate or relevant to the drug’s true value.

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The perspective about new drugs under development in groups outside the drug industry varies widely depending on the drug and the specific audience. A number of generalizations, however, can be made because different groups have differing frames of reference for looking at new drugs. 1. Patients Patients view new drugs in terms of hopes for improvement of symptoms, underlying disease, or risk factors. Cost of new therapy may also be a major consideration. More sophisticated patients will have at least some awareness of risks and the benefit to risk ratio present with the new therapy. 2. Regulatory authorities Regulatory authorities view new drugs from the nation’s health perspective in terms of potential health problems resulting from adverse reactions as well as potential benefits. Regulatory agencies often focus on worstcase scenarios. 3. Competitors Competitors within the drug industry view a new drug as a minor to major threat to their own marketed drugs and/or new investigational drugs. In some cases a company’s own development strategies will be markedly influenced by competitors, and in other cases the potential competitors will be ignored. Some perspectives of consumer advocates, trade associations, physicians, academicians, legislators, and other groups are discussed in the last section of this book. SYNOPSIS OF DRUG DISCOVERY AND DEVELOPMENT Drug Discovery

When asked for a definition of Hinduism one religious scholar said “It’s simple, anyone who says he is a Hindu is o n e . ” The reason for this statement is that Hinduism has not rejected or cast out beliefs of the past but has continued to build on them and to add new beliefs. Likewise, the processes of drug discovery are multifaceted and new ways of finding drugs are continually being added without discarding methods of the past. Thus, some people view drug discovery primarily in terms of the new methods of biotechnology, whereas others emphasize the importance of computer-assisted methods of drug discovery. Neither of these relatively new approaches is the major means of discovering novel drugs, nor are the oldest methods of random screening or haphazard trial and error that have been used for over 100 years. The major methods of discovering new drugs today are those used during the past 50 years. The most important method is the trial and error empirical approach. Novel compounds called analogues are made that are similar to marketed or known drugs. Other compounds are also made that are distantly related or totally unrelated to marketed or known drugs. These compounds are hypothesized to have biological activity and are then tested by empirical methods using relevant animal models. Some animal models are related to human disease. If the compound is found to have biological activity of interest it is called a chemical lead or a lead compound. If the lead is highly active it will stimulate chemists to make many new compounds that are chemically related to the lead compound. Eventually, a compound is hopefully found that has sufficient positive qualities and few negative qualities compared to

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existing therapy to justify additional animal studies. It is usually hoped that this compound will become a drug. This marks the end of the drug discovery period and the start of drug development. The compound is now considered as a candidate compound for drug development. The processes of drug discovery are not straightforward. There is a certain amount of disorder in the system. Too much order and control are usually considered detrimental, although there should be a sound rationale underlying the activities conducted. Many factors must be considered by scientists when choosing specific compounds to make and test. These issues as well as other methods of discovering drugs are discussed in Chapter 2. The one final method of drug discovery that must be mentioned is serendipity or accident. Mark Twain once aptly said that the greatest inventor of all was accident. Drug Development

Drug development is a highly complex process involving thousands of different activities. For the most part these activities are not described in this book, but may be found in references (see Bibliography). Figures 18.1 and 18.2 in the book Guide to Planning and Managing Multiple Clinical Studies (Spilker, 1987c) illustrates how many of these activities are interconnected. As opposed to drug discovery, where a certain degree and type of disorder is encouraged, drug development has order, organization, and discipline as goals. Too much disorder can be highly detrimental to the process of bringing a drug to market. After a candidate compound to be studied further as a potential drug is identified, we enter the world of drug development. Early activities of drug development involve an in-depth analysis of the candidate compound’s profile in additional animal studies. This period usually lasts from six to 18 months. If both the positive and negative attributes are acceptable, it means that the compound has a benefit to risk ratio adequate to pursue development. At that point the candidate compound is elevated to become a project compound, which means that it will be tested in humans if it can pass other preclinical requirements. Project compounds are developed by a project team whose members represent different departments within the company. The project compound progresses through technical development, toxicology, metabolism, and other animal studies until it receives a green light to be tested in humans. At the time of initial testing in humans a project compound becomes a project drug. There are three phases of clinical studies (see terminology page) that a drug passes through before it receives regulatory approval and may be sold as a marketed drug. In a few situations (e.g., drug for a life-threatening disease without adequate treatment, drug for a rare disease) Phase III may be omitted. The attrition rate from stage to stage is usually high. It is estimated that 10,000 compounds are synthesized for every 10 that reach the stage of human testing. Of these 10 compounds only one eventually reaches the market. The success rate of new compounds and projects is discussed further in Chapter 16. Terms used to describe the various stages a drug passes through (lead compound, candidate compound, project compound, project drug, marketed drug) are presented to clarify the various stages of discovery and development. These terms are not all in current use throughout the industry.

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Drug development involves a feedback loop to help future drug discoveries. Information on a project compound in preclinical studies may indicate a beneficial attribute or toxicological effect that may be hopefully accentuated in the former case or eliminated in the latter case. This information helps chemists design new (and hopefully better) compounds to make and test for their activity. A feedback loop also exists between the clinic and laboratory. Human data enables chemists to design and make better compounds that may eventually be tested as new drugs. Influence of Regulations on Drug Discovery and Development

Advances in science and changes in government regulations are the two most important factors to influence the discovery and development of drugs since the Second World War. Specific advances in science will not be discussed here, except to note that many breakthroughs in basic science have eventually led to discoveries of important new drugs. Many regulations have affected drug development but two of the most important are the 1938 Food, Drug, and Cosmetic Act, which mandated that drugs must be safe, and the 1962 Kefauver-Harris amendments to the 1938 Act. The latter amendments raised the standards for approval of new drugs, especially in terms of their efficacy. This has provided benefits to many patients who buy and take drugs. Because of these amendments, certain ineffective and partially effective drugs were removed from the market. On the other hand, there is a price paid for these gains: (1) fewer drugs are brought to market each year, (2) the time after a company submits a New Drug Application (NDA) to the FDA until its approval has grown significantly longer, (3) the higher standards have raised the costs of drug development, (4) the FDA has decreased the physician’s ability (according to some) to choose a drug to prescribe for patients as freely as in the past, and (5) a drug lag developed (i.e., there was a greater delay for introducing most drugs in the United States than in certain European countries). Golden Rules of Drug Development

Although the golden rules (i.e., important principles) of drug development are well known, most (if not all) drug companies are continually violating these principles. There are some exceptions to each of these principles, but if generally adhered to they will often save both years of unnecessary or inefficient work and large amounts of resources. Each of these 18 principles is described in detail elsewhere in this book or in the Guide to Clinical Studies trilogy (Spilker, 1984, 1986b, 1987c). The overriding principle of drug development is that activities may be planned, coordinated, and to some degree controlled using appropriate systems and methods— after the specific compound to be developed has been identified. The processes of drug discovery, however, are much less susceptible to planning or control. Attempts to control drug discovery often stifle and destroy the creative process. The following principles apply to drug development. 1. Focus development activities in a relatively limited number of therapeutic areas. There are few companies, if any, that can adequately develop drugs in all

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therapeutic areas. By focusing efforts, companies can develop areas of strength that help drug development, as well as drug discovery and drug marketing activities. 2. Formulate an overall concept and strategy of how each drug, indication, and formulation will be developed. Seek input from Marketing to help formulate various strategies. Establish minimal criteria that a drug must achieve to continue its development. Detailed strategies must be developed in several functional areas (e.g., marketing, research and development) and at several levels (e.g., individual sections and departments). Insure that an appropriate balance of effort is spent between developing, reviewing, and revising plans with efforts spent on carrying out the plans. See Chapter 2 and Guide to Planning and Managing Multiple Clinical Studies (Spilker, 1987c, Chapters 2 and 3). 3. Create an international development plan that minimizes duplication and stresses efficiency. Determine the appropriate balance between a lean plan that will generate the absolute minimal amount of data required for regulatory approval and a fat plan that goes far beyond what is required. See Chapter 19 and Guide to Planning and Managing Multiple Clinical Studies (Spilker, 1987c, Chapter 13). 4. Avoid tangents that depart from the chosen path of development, except when (a) the tangent is to become the new path (i.e., a new strategy is adopted) or (b) the tangent is carefully reviewed before it is implemented and is considered worthy of pursuit. The tangent is then incorporated into the existing strategy. See Chapter 4 and Guide to Planning and Managing Multiple Clinical Studies (Spilker, 1987c, Chapter 3). 5. Hire the best people possible for all positions in a company even at the most junior level. Appropriately train and orient staff in both methods and ethos of the company. Do not appoint academic scientists or government administrators to head a drug company’s research and development division, unless they are highly experienced in drug discovery and development. See Chapters 7 and 12. 6. Assign personnel and other resources according to both the value and the importance of each indication and formulation being developed. Scientific, medical, and commercial values must be considered, although each are not of equal importance. Consideration must also be given to other drugs in the portfolio. See Chapters 14 through 16. A balance must be achieved between placing almost all resources on a few projects and spreading resources thinly across many projects. 7. Do whatever is necessary to encourage openness, honesty, cooperation, teamwork, and shared goals between functions (e.g., research and development, marketing, production). Achievement of these goals depends on trust, accurate communications, and the creation of a positive working environment. Disseminate appropriate information both upwards and downwards throughout the company. Stress the concept of sharing information and avoiding surprises whenever possible. See Sections II and 111 of this book. 8. Adhere to the highest standards of ethics in scientific, medical, marketing, and other activities. This behavior will provide numerous benefits to the company in terms of regulatory reviews and ability to respond to questions, criticisms, and accusations from external sources, besides providing a strong motivating factor to staff. 9. Create and use systems and standard operating procedures that assist the development processes. Do not allow systems to become bureaucracies, restrain development, or compromise efficiency. Each chapter in this book discusses aspects of this theme. Utilize computer systems that are either identical or compatible between each major site of a company developing drugs.

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10. Develop a portfolio of investigational drugs that balances high- and low-risk projects, and include drugs that will be developed in both a long-term and shortterm time period. Attempt to have some projects that have a chance of becoming breakthrough drugs. 11. Reevaluate each project and the overall portfolio on a relatively frequent periodic basis. Reviews must be objective. Reviewers must not be misled by a strong desire of some or many people for a drug to be effective and safe with the actual demonstration of a sufficient amount of hard data of appropriate magnitude that it actually is effective and safe. Insure that all appropriate managers and workers understand current priorities of the research and development division as well as the priorities of their specified department, insofar as the two differ. 12. Identify the rate-limiting steps of each drug’s development. Insure that appropriate and adequate resources and attention are focused on these areas. 13. Develop a clear licensing policy and strategy that allows all product, technology, and other opportunities (e.g., acquisitions) to be rapidly reviewed and assessed for possible benefit to the company. This includes both licensing-in and licensing-out opportunities. Establish alliances with other companies (e.g., joint ventures) that enhance drug development activities. See Chapter 26. 14. Attempt to create and maintain a cooperative relationship with the FDA and other regulatory authorities. Regulatory guidelines must be viewed as guidelines and not requirements. In discussions with regulatory authorities it is necessary to differentiate between real demands or requirements, imagined demands, suggestions, and hearsay. See Chapter 25. 15. Prepare logical and straightforward regulatory submissions. Lead the regulatory reviewer step-by-step through each aspect of the application. D o not make reviewers work hard to understand the content of the application and the company’s logic in proceeding in a specific direction. Be up-front with any problems in the application and do not attempt to hide bad data. When it is reasonable to perform multiple analyses of data, conduct most, if not all. Include complete analyses of the most relevant ones (one) and summaries of less important ones in regulatory applications. Indicate the reasons why a particular analysis is preferred (if that is the case). See Chapter 25. 16. Protect and extend the drug’s indications and formulations after initial marketing. Protection may include conducting additional clinical studies, synthesizing additional compounds, or conducting postmarketing studies. Extension of a product’s available formulations, approved indications, and current packaging usually enhances appropriate medical uses of a drug and improves its commercial returns. 17. Attempt to learn everything of importance about a drug, even what may be considered as bad news. It is vital for a company to know as much important and relevant information as possible about their drugs. This enables them to deal most effectively with questions, criticisms, and accusations. 18. Insure that activities to implement and carry out each of these principles follow an appropriate pace. If any of these principles is pushed too rapidly then the quality of the results will suffer, problems will arise, mistakes will be made, and waste occur. If the pace of development is too slow, then valuable patent life will be lost and competitive drugs may overtake one’s own drug. The balance desired should involve conducting appropriate activities simultaneously at a rapid pace that may be followed in an efficient manner. The pace should not be so rapid or pressures applied that

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encourage professionals to cut corners or make unwarranted assumptions about a drug’s efficacy or safety. Other important principles could be included in this list. Their omission does not signify that their importance is any less than the 18 included, especially in specific situations. Each individual department or function involved in drug development could also create their own list of general or more specific golden rules. Decisions that influence a drug’s development should b e based o n logical, practical, and other rational considerations that consider the company’s past, present, and future. It is hoped that progressively fewer decisions are based on emotions, whims, political considerations, or for other personal reasons. Implementing These Golden Rules Merely understanding and believing in the golden rules described is not sufficient to have them realized. It is also necessary to have a competent group of managers who are able to put these rules into practice. There is a final step required beyond understanding, acceptance, and having competent staff. That step is the collective will, and desire to have these principles followed and become the ethos of drug development. The attitudes most conducive to efficient drug development must be present throughout the organization, not only in the research and development division where these principles are most important. It may be possible for a company to develop drugs efficiently if there are one or two senior research and development managers who d o not share the attitudes described or who d o not believe in the golden rules. But, if more than a small number of senior managers or if senior managers in critical positions do not share these beliefs, the entire development process will be adversely affected. A company operating with one or more albatrosses about its collective neck must shed them or risk the undesirable consequences of inefficient drug development. The correct attitude toward developing drugs involves a positive view that may be expressed as “ W e will do whatever is necessary to insure that we meet realistic plans and targets.” This attitude requires a commitment of staff to: 1. Identify the most pertinent issues and problems to address. Discuss these issues and problems appropriately before initiating action. 2. Make active decisions and not allow decisions to be made by avoiding issues. 3. Cooperate as fully as possible with all relevant individuals who are members of a drug development team. Attitudes toward drug development are described more fully in Chapter 7. METAPHORS OF DRUG DISCOVERY AND DEVELOPMENT

Because the processes of drug discovery and development are so complex there are often times when it is useful to describe them using metaphors or analogies. These metaphors are described because they are an easy way to conceptualize many of the processes of drug discovery or development. There is no single metaphor or

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SELECTED METAPHORS O F DRUG DISCOVERY A N D DEVELOPMENT

Horse Race

Poker Game

Ocean Liner Orchestra

TRUE IMAGE Maze Pipeline

Connectthe-Dots

Hurdles Race High Jump

Fig. 1.1. Selected metaphors of drug discovery and development. The true image for a particular d r u g is a combination of some or all of these metaphors.

analogy that is entirely appropriate or best and many have been used (Fig. 1.1). The metaphors described are (1) pipeline, (2) horse race, (3) poker game, (4) orchestra, (5) hurdles race, (6) ocean liner, (7) connect-the-dots, (8) maze, and (9) high jump. The pipeline metaphor refers to both discovery and development, the maze refers to only discovery, the orchestra and connect-the-dots only to development, and the others may refer to either discovery or development. Managers often have one or two that they particularly favor. In some situations one metaphor may stand out and capture its essence. Pipeline of Drug Discovery, Development, and Marketing

The overall picture of drug discovery and development has sometimes been described as a pipeline with three main parts: drug discovery, drug development, and

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drug marketing (Fig. 1.2). Drug discovery originates with ideas and new chemicals and includes biological testing in various animal models. Eventually, one or more chemicals emerge as a significant lead (i.e., an important compound to evaluate further and to use as a model to make other related compounds). These leads advance through many stages of preclinical biological testing, and if they do not falter they are evaluated in humans. Clinical evaluation, toxicology, and preclinical studies continue up to the point of the regulatory submission of a New Drug Application (NDA). A myriad of interactions, feedback loops, and other activities continue throughout this process. Thus, drug development should be viewed as a dynamic system that has various bulges of activities and bottlenecks, and not as a rigid pipeline. As a simple exercise, try to imagine the development activities of a single drug (i.e. , a single project) as it travels through the pipeline. The first stage is the discovery of the compound that will proceed through the pipeline. This may take any number of years, because there is no way to predict when (or if) a discovery will be made. The usual range would be from 1 to 12 years for most drugs. Once the compound is identified, activities are initially begun in some preclinical science departments to evaluate the compound’s profile and safety in detail. Eventually, more departments become involved (e.g., chemical scaleup, formulations, statistics, regulatory affairs) as the compound progresses along the pipeline. Some departments remain active throughout a project’s life, while others may be active for only a limited period. This major pipeline is really composed of many smaller pipelines or subpipelines, within a single department or single function. A few of these are shown in Fig. 1.3. The typical time period required to take a drug through the pipeline after it has been identified and chosen for development is 8 to 12 years (Table 1.1). The single project described may be major in terms of resources required and it may stretch the capacity of the company’s resources as it travels along the pipeline. When a major project is being developed, the pipeline is sometimes viewed like a snake that has swallowed a large ball. A ‘"visible” bulge passes progressively through its body. The resolution of temporary bottlenecks (i.e., areas that have insufficient personnel or other resources and have created a large backlog of work) often may be expedited with temporary staff or novel solutions. In practice, the overall pipeline within a company involves more than a single drug, because many projects are pursued simultaneously. Imagine a long snake that has swallowed not one project, but 40 or more. Some are small and others far greater in magnitude. In addition to adding new projects to the system, other projects are expanding, and still others are being terminated. New regulations also have a marked influence on many of the activities within this pipeline by influencing which areas of the snake must expand or change. T o address many of these issues, a company must monitor what is occurring at each part of the pipeline (i.e., within various departments) and insure that each department is prepared for the projects that are heading toward it. Sometimes it is necessary to add more staff because of markedly increased work loads. But, there are many other solutions that may also be tried in attempting to maintain the balance among the work load of groups active in drug development. These solutions include reassigning personnel, hiring temporary staff, contracting work to outside groups, and delaying some projects. Other factors to consider include building new facilities, purchasing new equipment, and licensing drugs in (or out). As a result of this dynamic